The dental follicle, a loose connective tissue sac which surrounds the tooth, is required for eruption, and along with the adjacent stellate reticulum (SR), contains genes coding for the probable eruption molecules. A cascade of molecular signals in which there is cross-talk between the follicle and SR may initiate the cellular events of eruption; namely, early postnatal recruitment of mononuclear cells to the follicle to form osteoclasts needed for bone resorption to form the eruption pathway. Thus, it is the objective of this proposal to determine if certain of these molecules present in vivo are required for eruption and what is the role of such molecules in initiating the cellular events. To that end, monocyte chemotactic protein-1 (MCP-1), a molecule present in the dental follicle, will be injected into rats to determine its effect on the time of eruption and its ability to recruit the mononuclear cells into the follicle. The ability of the follicle cells to secrete MCP-1 in response to other putative eruption molecules also will be determined. Two molecules present in the SR, interleukin-1alpha (IL-1alpha) and parathyroid hormone related protein (PTHrP), may signal molecules in the follicle to initiate eruption. Injections of these molecules, use of null mice devoid of the receptor gene for IL-1alpha, and analysis of gene expression by RT-PCR and ribonuclease protection assay techniques all will be used to determine if these molecules are necessary for eruption, as well as determining how they affect gene expression and mononuclear cell numbers. Gene expression and immunolocalization of interleukin-6 in the follicle also will be examined. By determining what local molecular signals are required for eruption, an understanding of why teeth sometimes do not erupt (e.g., third molars in humans) may be gained. In turn, molecular treatment may someday be used to induce impacted teeth to erupt, as well as perhaps initiate tooth movement that often is required in orthodontics. Additionally, because bone resorption is required for eruption, these studies also will provide answers about the molecular basis of alveolar bone resorption, an understanding of which is critical in treatment of periodontal diseases.